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Am J Hum Genet. 2018 Jul 5;103(1):74-88. doi: 10.1016/j.ajhg.2018.05.011. Epub 2018 Jun 28.

MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse.

Author information

1
Hearing and Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
2
Institute of Biomedical Research "Alberto Sols," Spanish National Research Council-Autonomous University of Madrid, 28029 Madrid, Spain; Center for Biomedical Network Research in Rare Diseases, Institute of Health Carlos III, 28029 Madrid, Spain; Hospital La Paz Institute for Health Research, 28029 Madrid, Spain.
3
Hearing and Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
4
Institute of Biomedical Research "Alberto Sols," Spanish National Research Council-Autonomous University of Madrid, 28029 Madrid, Spain; Center for Biomedical Network Research in Rare Diseases, Institute of Health Carlos III, 28029 Madrid, Spain.
5
Hearing and Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
6
Center for Biomedical Network Research in Rare Diseases, Institute of Health Carlos III, 28029 Madrid, Spain; Servicio de Genetica, Hospital Universitario Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
7
Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Neurology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
8
Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
9
Department of Ophthalmology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
10
The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
11
Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Ophthalmology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
12
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
13
Hearing and Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Institute of Health Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
14
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
15
Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
16
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
17
Hearing and Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: hannie.kremer@radboudumc.nl.

Abstract

In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons.

KEYWORDS:

Deiters cells; MPZL2; cochlea; deafness; hair cells; hearing impairment; human; mouse

PMID:
29961571
PMCID:
PMC6037131
[Available on 2019-01-05]
DOI:
10.1016/j.ajhg.2018.05.011

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